Transfusion Of Cellular Blood Components Research Articles

Transfusion-associated graft-versus-host disease: an update

Graft-versus-host disease not associated with stem cell transplantation is a rare event, but might be underdiagnosed. It occurs mainly as transfusion-associated graft-versus-host disease in a susceptible recipient between day 2 and 30 after transfusion of cellular blood components, which also contain lymphocytes. These transfused lymphocytes are the causative agents. Their major target is the bone marrow, resulting in bone marrow failure leading to pancytopenia and consecutive death. The fatality rate is high (approximately 90 %). Patients at risks are those with congenital or acquired immunodeficiencies. However, immunocompetent patients may also be affected. This is the case when human leukocyte antigen (HLA)-homozygous donors share one haplotype with the recipient or when HLA-matched components are selected. The diagnosis is mainly a clinical one, supported by laboratory findings in biopsies from the skin and bowel. The detection of chimerism by HLA typing or short tandem repeat polymorphism can confirm the diagnosis. So far, no reasonable treatment exists, so prevention is still the only effective measure. Gamma irradiation has been used for years with great success. However, also pathogen inactivation, although developed to minimize the infectious risk of blood components, has shown, as a beneficial by-product, to reduce the number of lymphocytes. Other graft-versus-host diseases not associated with stem cell transplantation are those occurring after solid organ transplantation, e.g., after liver or small bowel transplantation, which have a similar pathophysiology and bad prognosis.

Human T‐lymphotropic virus lookback in NHS Blood and Transplant (England) reveals the efficacy of leukoreduction

Leukoreduction of blood components was introduced in the United Kingdom during 1998. Human T-lymphotropic virus (HTLV) screening of blood donations was introduced in 2002. NHS Blood and Transplant conducted an HTLV lookback on blood components issued before 2002. A proportion of included components were nonleukoreduced, although the majority were subject to white blood cell reduction measures. A standard lookback was conducted on untested cellular blood components from donors later confirmed to be HTLV positive, for the 4 to 5 years before 2002, and on the last tested negative donation from donors who had seroconverted. A total of 437 red blood cell and platelet components were included and an outcome was reported for 84% of these. Just over half of identified recipients were dead at the time of lookback; blood samples for testing were obtained from 77% of identified living recipients. HTLV infection was confirmed in seven recipients, but one was discounted as not transfusion transmitted. Although numbers are small, our results provide evidence of the efficacy of leukoreduction in reducing the likelihood of HTLV transmission through transfusion of cellular blood components. The HTLV-positive rate in recipients of leukoreduced components was 3.7%, a reduction of 93% compared with nonleukoreduced components. Importantly, the one infected recipient of a leukoreduced component had existing risk factors for HTLV infection. HTLV lookback was much less efficient in identifying infected recipients than was hepatitis virus C lookback.

Survey of current practice for prevention of transfusion-transmitted cytomegalovirus in the United States: leucoreduction vs. cytomegalovirus-seronegative

Cytomegalovirus (CMV) is a significant pathogen transmissible through blood transfusion that can have devastating effects on immunocompromised patients. Current transfusion practice provides two choices for transfusion of cellular blood components that reduce the risk of transfusion-transmitted CMV (TT-CMV): blood components collected from CMV seronegative donors and leucocyte-reduced (LR) blood components. A web-based survey was designed and administered to AABB physician members in April 2007 to collect information regarding current blood banking and clinical practices for prevention of TT-CMV in the United States. Individuals representing 183 different institutions completed the entire survey (an institutional response rate of 32.5%). Sixty-five percent of respondents indicated that their institution considered that CMV-seronegative and LR products are equally effective in preventing TT-CMV. When analyzed by institutional type, academic institutions and community hospitals were more likely to subscribe to the premise that LR blood components are equally effective at preventing TT-CMV, than were community blood centres and government institutions. However, reported practices for specific patient populations did not match this view of equivalence between CMV-seronegative and LR products with many patient populations preferentially receiving CMV-seronegative components. Fetal and neonatal populations were more likely than other patient populations to receive CMV-seronegative products to reduce the risk of TT-CMV. There is wide variability in transfusion practices to reduce the risk of TT-CMV. Lack of a consensus approach may reflect the conflicting data that exist in the literature as well as adherence to longstanding practice.

Transfusion‐associated graft‐versus‐host disease

Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of transfusion of cellular blood components producing a graft-versus-host clinical picture with concomitant bone marrow aplasia. The disease is fulminant and rapidly fatal in the majority of patients. TA-GvHD is caused by transfused blood-derived, alloreactive T lymphocytes that attack host tissue, including bone marrow with resultant bone marrow failure. Human leucocyte antigen similarity between the transfused lymphocytes and the host, often in conjunction with host immunosuppression, allows tolerance of the grafted lymphocytes to survive the host immunological response. Any blood component containing viable T lymphocytes can cause TA-GvHD, with fresher components more likely to have intact cells and, thus, able to cause disease. Treatment is generally not helpful, while prevention, usually via irradiation of blood components given to susceptible recipients, is the key to obviating TA-GvHD. Newer methods, such as pathogen inactivation, may play an important role in the future.

European strategies against the parasite transfusion risk

Protozoal infections are endemic in mainly tropical low income countries, affecting millions of people. Malaria, American trypanosomiasis ( Trypanosoma cruzi/Chagas disease) and protozoal tickborne diseases (e.g. Babesia) can be efficiently transmitted by transfusion of cellular blood components. In non-endemic areas like Europe malaria, Chagas disease and Babesia are imported diseases resulting of travelling to endemic areas and migration of autochthons from these endemic areas. A recent International Forum showed that in Europe, as well as the USA, prevention of transfusion-associated protozoal infections depend mainly on selection of donors using questionnaires. Most countries divide donors at risk for malaria in two groups: individuals who have lived in the first 5 years of their life in malaria endemic areas and those who are borne and residing in non-endemic areas and visited the endemic area(s). The first category of donors is rejected for 3 years after their last visit to the endemic area, and in one country such donors are permanently rejected. In some countries such donors are accepted after 4 months–3 years, provided a test for malaria is non-reactive. Persons from non-endemic areas, who visited the malaria endemic area, are rejected for 4–12 months. Some countries reject these donors for 3 years or permanently when they resided for more than 6 months in the endemic area. The rejection rate of donors for malaria risk in the various countries was 0.003–0.43% of all donations. Over the last decade only a few cases of TT-malaria were reported in the various countries. In several countries donors are questioned for risk of T. cruzi infection. In some countries donors are excluded when they (or their mothers) were born in South or Central America, if they received a blood transfusion in these areas and if they lived in rural areas in these endemic countries for more than 4 weeks. In none of the countries donors are asked if they had Babesia or Leishmania. At present implemented measures to prevent TT-malaria in the European countries are probably highly effective. More research is needed to establish the theoretical risk of TT- T. cruzi and TT- Leishmania infection in Europe, before preventive measures may be considered.

Risks associated with transfusion of cellular blood components in Canada

We provide a comprehensive review of risks associated with allogeneic red blood cell and platelet transfusions in Canada. The review focuses on clinically symptomatic noninfectious transfusion risks (acute and delayed hemolytic, febrile nonhemolytic [FNHTR], allergic, volume overload, transfusion-related acute lung injury, graft-versus-host disease, and posttransfusion purpura) and the risk of clinically significant disease from transfusion-transmitted infections. Data sources include information from Canadian Blood Services, Héma-Québec, Health Canada, and the Québec Hemovigilance System as well as published information from research studies and international hemovigilance systems. We estimate that in 2000 the aggregate risk of potentially severe reactions (excluding FNHTR and minor allergic reactions) was 43.2 per 100,000 red cell units (95% confidence interval [Cl]: 38.7–48.1), affecting 337 recipients, and 125.7 per 100,000 platelet pools of 5 units (95% Cl: 100.8–154.9), affecting 88 recipients. The most frequent potentially severe outcomes for red cell transfusion were hemolytic reactions and volume overload and for platelet transfusion were major allergic reactions and bacterial contamination. The current risk of human immunodeficiency virus and hepatitis C virus transmission is approximately 1 in 4 million and 1 in 3 million units, respectively. These estimates are useful for decisions concerning transfusion therapy, the informed consent process, and for evaluating efficacy of interventions to reduce risk.

Risks associated with transfusion of cellular blood components in Canada.

We provide a comprehensive review of risks associated with allogeneic red blood cell and platelet transfusions in Canada. The review focuses on clinically symptomatic noninfectious transfusion risks (acute and delayed hemolytic, febrile nonhemolytic [FNHTR], allergic, volume overload, transfusion-related acute lung injury, graft-versus-host disease, and posttransfusion purpura) and the risk of clinically significant disease from transfusion-transmitted infections. Data sources include information from Canadian Blood Services, Héma-Québec, Health Canada, and the Québec Hemovigilance System as well as published information from research studies and international hemovigilance systems. We estimate that in 2000 the aggregate risk of potentially severe reactions (excluding FNHTR and minor allergic reactions) was 43.2 per 100000 red cell units (95% confidence interval [CI]: 38.7-48.1), affecting 337 recipients, and 125.7 per 100000 platelet pools of 5 units (95% CI: 100.8-154.9), affecting 88 recipients. The most frequent potentially severe outcomes for red cell transfusion were hemolytic reactions and volume overload and for platelet transfusion were major allergic reactions and bacterial contamination. The current risk of human immunodeficiency virus and hepatitis C virus transmission is approximately 1 in 4 million and 1 in 3 million units, respectively. These estimates are useful for decisions concerning transfusion therapy, the informed consent process, and for evaluating efficacy of interventions to reduce risk.

Bacterial contamination of blood products

Transfusion-associated septic reactions occurring during, or following, the transfusion of cellular blood components was one of the earliest recognised complications of allogeneic blood transfusions. The presence of bacteria in cellular blood products thus has been a problem for many decades and currently it is probably the most common microbiological cause of transfusion-associated morbidity and mortality.

New technologies for the inactivation of infectious pathogens in cellular blood components and the development of platelet substitutes

Despite the increased safety of blood components, achieved through improved donor selection and testing, transfusion recipients remain at risk of transfusion-associated diseases. Transfusion of cellular blood components has been implicated in transmission of viral, bacterial and protozoan diseases.1 While it is commonly recognized that hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), and retroviruses, such as human immunodeficiency virus (HIV) and the human lymphotrophic viruses (HTLV), can be transmitted through cellular components, other pathogens are emerging as potentially significant transfusion-associated infectious agents. For example, transmission of protozoan infections due to trypanosomes2 andBabesia have been reported.5 In addition to viral and protozoan infectious agents, cases of bacterial contamination of platelet and red cell concentrates continue to be reported 6,7 and may be an under-reported transfusion complication.8 More importantly, new infectious agents continue to enter the donor population, and there is an inherent time delay before the new pathogens are definitively identified and new tests implemented in order to maintain consistent safety of the blood supply. The paradigm for this problem is the HIV pandemic.During the past decade a number of methods for inactivating infectious pathogens in platelet concentrates have been investigated as a strategy to improve the safety of platelet transfusion therapy. One method of treating platelet concentrates to inactive pathogens has now reached the advanced clinical trial phase in the United States and Europe. Similar efforts with a new class of compounds are underway for red cell concentrates, and two of these are in early phase trials. In addition to studies with allogeneic platelets and red cells, a number of laboratories have described methods for developing platelet substitutes or modified platelets to avoid the use of traditional platelet concentrates as a means to improve safety.

Characterization of reactions after transfusion of cellular blood components that are white cell reduced before storage

During the storage of cellular components before transfusion, cytokines that may mediate transfusion reactions are released from white cells (WBCs). Adverse effects of transfused cellular blood components therefore depend not only on the number of residual WBCs in blood components, but also on the timing of WBC reduction. Febrile nonhemolytic transfusion reactions (FNHTRs), allergic reactions, and other reactions were characterized in recipients of 4728 units of red cells (RBCs) and 3405 bags of single-donor apheresis platelets (SDAPs), all of which underwent prestorage WBC reduction. To delineate the impact of prestorage versus poststorage WBC reduction of RBCs on transfusion reactions, these results were compared with reactions occurring after the transfusion to similar recipients of 6447 bags of RBCs that underwent poststorage WBC reduction by bedside filtration and 5197 units of SDAPs that underwent prestorage WBC reduction. The levels of interleukin (IL) 1 beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured in a subset of 20 implicated cellular blood components at the time of transfusion reactions and correlated with the duration of storage before transfusion. The incidence of reactions was greater after transfusions of SDAPs (5.49%) than of RBCs (1.63%). The incidence of FNHTRs after transfusion of RBCs that were WBC reduced before storage (1.1%) was significantly lower (p = 0.0045) than that after transfusion of RBCs that were WBC reduced after storage (2.15%). Although allergic reactions to RBCs that were WBC reduced before storage were also less common (0.41%) than those to RBCs that were WBC reduced after storage (0.51%), the difference was not significant (p = 0.067). At the time of reactions to RBCs and SDAPs that were reduced before storage, the level of IL-6 was negatively correlated (r = -0.54, p = 0.014) with the duration of storage before transfusion, and there was no correlation between the level of either IL-1 beta or IL-8 and the interval before transfusion. TNF-alpha was not detectable in any implicated component. FNHTRs, but not allergic reactions, were less common after transfusion of RBCs that were WBC reduced before storage than after the transfusion of those WBC reduced after storage at the bedside by filtration. The level of IL-6 in implicated cellular blood components that were WBC reduced before storage was inversely correlated with the length of storage before transfusion. Further studies are needed to determine whether the transfusion of cellular blood components that were WBC reduced before storage can both diminish the incidence of adverse reactions and improve outcome.

Transfusion-associated graft-versus-host disease and its prevention

Transfusion-associated graft-versus-host disease is a rare but usually fatal complication of transfusion of cellular blood components, caused by multiorgan engraftment and proliferation of donor T lymphocytes. The classical features of skin rash, diarrhoea and hepatitis, along with striking bone-marrow failure, are seen 1–2 weeks after transfusion. Although early reports described the condition only in immunusuppressed individuals, sharing of an HLA haplotype between donor and an immunocompetent recipient can also result in transfusion-associated graft-versus-host disease. The condition is entirely preventable by gamma irradiation of cellular blood components to 25 Gy, although this results in some reduction of red-cell viability and increased loss of red-cell potassium. The major indications for irradiated blood components include bone marrow/stem cell auto- or allografting, Hodgkin's disease, intrauterine transfusions, and transfusions from relatives or HLA-selected platelet donors.

Current Practice and Guidelines for the Transfusion of Cellular Blood Components in the Newborn

THE FREQUENCY OF blood component transfusions, in particular that of red celI (RBC) concentrates, to premature neonates is amongst the highest of any patient group in tertiary level hospitals. In one study, out of atotai of 4,906 neonates, 120 (2.5%) received bIood transfusions with over two-thirds of those receiving multiple transfusions. 1,3 Infants with birthweights of <1500 g almost invariably receive blood transfusions. 1,2,3 Although the volume of blood transfused to each neonate is smalI, the number of transfusions administered, and consequently the number of donor exposures, is high. In one study, neonates < 1250 g were exposed to a mean of 10.5 donors,3 and in a second study to 8.9 donors. 1 The rate of donor exposures per infant, as reported from several investigators, is presented in Table 1. Concems about transfusion transmitted infectious diseases, including the Human Immunodeficiency virus, have been associated with fewer transfusions (and donor exposures) in adults. However, blood usage and donor exposures continue to be high in neontai intensive care practice. This may reflect the need for aggressive resuscitative measures to saIvage extremely premature infants. CIearly premature neonates are unique. Because of their smalI blood volumes, a major indication for transfusions of RBC concentrates is to replace blood Iost via iatrogenic phIebotomy-bleeding into the lab. 5,6 A concerted effort should be made to reduce donor exposure. Several mechanisms have been suggested, of which the most important are the judicious use of transfusion therapy, the establishment of recognized guidelines for transfusion therapy in the newborn, the implementation of innovative methods to use fewer donors and the further development of laboratory microtechnology.7 In many instances, the need for blood transfusion is unquestioned (eg, exchange transfusion for hyperbilirubinemia and RBC concentrates for anemia that has caused cardiopulmonary compromise). However, in some cases it is apparent that the indications, the associated risks and the optimum blood product for transfusion have not been adequately defined for the neonatal population. 8 ,9,10 This report will review the current